This research article published by Hindawi, 2020Brucellosis is a zoonotic infection caused by Gram-negative bacteria of genus Brucella. The disease is of public health, veterinary, and economic significance in most of the developed and developing countries. Direct contact between susceptible and infective animals or their contaminated products are the two major routes of the disease transmission. In this paper, we investigate the impacts of controls of livestock vaccination, gradual culling through slaughter of seropositive cattle and small ruminants, environmental hygiene and sanitation, and personal protection in humans on the transmission dynamics of Brucellosis. The necessary conditions for an optimal control problem are rigorously analyzed using Pontryagin’s maximum principle. The main ambition is to minimize the spread of brucellosis disease in the community as well as the costs of control strategies. Findings showed that the effective use of livestock vaccination, gradual culling through slaughter of seropositive cattle and small ruminants, environmental hygiene and sanitation, and personal protection in humans have a significant impact in minimizing the disease spread in livestock and human populations. Moreover, cost-effectiveness analysis of the controls showed that the combination of livestock vaccination, gradual culling through slaughter, environmental sanitation, and personal protection in humans has high impact and lower cost of prevention.